Skin and pulmonary fibrosis result in substantial morbidity in scleroderma (systemic sclerosis, SSc). Furthermore, interstitial lung disease (ILD) culminating in pulmonary fibrosis is a major cause of death among scleroderma patients. Studies from our laboratory and others implicate the coagulation system, most notably the serine protease thrombin, in the pathogenesis of SSc-ILD. Thrombin can transform normal lung fibroblasts to a scleroderma fibroblast phenotype (e.g., myofibroblast features with high contractility and high collagen synthesis). Dabigatran etexilate is a selective thrombin inhibitor which is FDA-approved for the prevention of thromboembolic complications in patients with atrial fibrillation. Its mode of action differs from that of warfarin, a different anticoagulant tht has been shown not to be effective in treating idiopathic pulmonary fibrosis (IPF). We have strong preclinical in vitro and animal data demonstrating that thrombin inhibition by dabigatran etexilate ameliorates lung fibrosis at doses that do not perturb hemostasis. We, as well as other experts in the field of lung fibrosis, believe that dabigatran etexilate needs to be studied as a potential anti-fibrotic agent for the treatment of SSc-ILD and IPF. A necessary first step toward a phase 3 RCT and the primary aim of this proposal is to establish the safety of dabigatran in SSc-ILD patients. We will also conduct exploratory studies of the potential effects of dabigatran on the skin and lungs, including effects on the biological activity of thrombin in plasma and bronchoalveolar lavage fluid, as well as on the biologic behavior of SSc skin and lung fibroblasts. Our long-term goal is to determine whether or not our fundamental results will translate to a potential clinical intervention for SSc-ILD which can be tested in a future randomized control trial. This proposal addresses the essential need to develop disease modifying drugs and the current lack of safe and effective anti-fibrotic drugs for SSc, both of which are significant unmet needs in the treatment of this often fatal disease.